tbuckley/cabot-search huggingface dataset:
P11.67.B A RETROSPECTIVE STUDY OF 222 PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA - OUTCOMES INDICATIVE OF IMPROVED SURVIVAL OVER TIME
Authors: O Bairey, E Lebe, C Buxbaum, T Porges, A Taliansky, R Gurion, N Goldschmidt, T Tzuk Shina, M Zektser, L Hofstetter, T Siegal
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary central nervous system lymphoma (PCNSL) is a rare disease with an incidence of 0.4/per 100,000 person-years. As there is a limited number of prospective randomized trials in PCNSL, large retrospective studies on this rare disease may yield information that might prove useful for the future design of randomized clinical trials. MATERIAL AND METHODS We retrospectively analyzed the data of 222 newly diagnosed PCNSL patients treated in 5 referral centers in Israel between 2001-2020. During this period, combination therapy became the treatment of choice, rituximab has been added to the induction therapy, and consolidation with irradiation was largely laid off and was mostly replaced by high-dose chemotherapy with or without autologous stem cell transplantation. RESULTS Patients older than 60 comprised 67.5% of the study population. First-line treatment included high-dose methotrexate (HD-MTX) in 94% of patients with a median MTX dose of 3.5gr/m2 (range 1.14-6 gr/m2) and a median cycle number of 5 (range 1-16). Rituximab was given to 136 patients (61%) and consolidation treatment to 124 patients (58%). Patients treated after 2012 received significantly more treatment with HD-MTX and rituximab, more consolidation treatments, and autologous stem cell transplantation. The overall response rate was 85% and the complete response (CR)/unconfirmed CR rate was 62.1%. After a median follow-up of 24 months, the median PFS and OS were 21.9 and 43.5 months respectively with a significant improvement since 2012 (PFS:12.5 vs. 34.2 p=0.006 and OS:19.9 vs 77.3 p=0.0003). A multivariate analysis found that the most important factors related to OS were obtaining a CR followed by rituximab treatment and ECOG performance status. CONCLUSION The observed improvement in outcomes may be due to multiple components such as an intention to treat all patients regardless of age with HD-MTX- based combination chemotherapy, treatment in dedicated centers, and more aggressive consolidation with the INTRODUCTION of HDC-ASCT.
P10.33.A TARGETED INHIBITION OF THREE MAJOR PROLIFERATION PATHWAYS IN GLIOBLASTOMA INDUCES SENESCENCE THROUGH A MITOCHONDRIA-DEPENDENT MECHANISM
Authors: C Baltira, I Mayayo-Peralta, M Guillén-Navarro, B Thijssen, F Alkan, K Pello, D M Fedorushkova, A Their, J Silva, F Jochems, O Bleijerveld, H Janssen, W J Faller, R Bernards, M C de Gooijer, O van Tellingen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma (GBM) is a fatal brain tumor with a great unmet need for better therapies. Research on the genomic landscape of GBM has revealed that three major proliferation pathways — the PI3K-mTOR-AKT, the MAPK, and the CDK4/6-RB pathways — are overactive in the majority of GBM patients. Based on that knowledge we have developed a multi-target combination therapy (MTCT) by employing inhibitors of these three pathways. When these inhibitors are used in combination, lower, clinically more relevant concentrations of each drug are sufficient for target inhibition and proliferation arrest than with single agents.Excitingly, we find that MTCT not only shuts down proliferation but also causes permanent growth inhibition by the induction of senescence and the secretion of a senescence-associated secretory phenotype (SASP). MATERIAL AND METHODS Senescence is identified in a multimodal way, including morphological characterization, SASP production, beta-galactosidase activity, and colony outgrowth potential. RNAseq together with (phospho)proteomics are also applied to investigate the molecular mechanism in combination with techniques such as DNA damage assays, flow cytometry, western blot, metabolic assays, and fluorescence microscopy. RESULTS MTCT-senescent cells have increased mitochondrial reactive oxygen species (mtROS). However, they do not acquire nuclear DNA damage but only local mitochondrial DNA damage. Addition of antioxidants that deplete mtROS resulted in senescence rescue both in terms of morphology and proliferation arrest. MTCT-senescent cells display an enhancement in total mitochondrial mass, mitochondrial DNA copy numbers, and the transcription of mitochondrial proteins. Despite this enhancement, the basal respiration rate of these cells is comparable to untreated cells, indicating an impaired maximal respiration capacity in MTCT-senescent cells. Concordantly, these cells display striking disturbances of their mitochondrial network.Intriguingly, depletion of functional mitochondria prevents the induction of mtROS and senescence by MTCT but not by classical senescence inducers such as ionizing radiation or high concentrations of CDK4/6 inhibitors. CONCLUSION MTCT induces senescence in GBM cells through a unique nuclear DNA damage-independent mechanism for which the mitochondria are essential.
JS05.6.A CONTINUOUS DYNAMIC MAPPING OF LANGUAGE FUNCTION AND COGNITIVE CONTROL AND SPATIAL CORRELATION TO WHITE MATTER TRACTS USING INTRAOPERATIVE MRI TRACTOGRAPHY
Authors: A A Mughal, Ø Ø Holthe, K Olsen, M Nævra, G Løvland, S Vatnehol, R Undseth, A Espinoza, L Etholm, E O Vik-Mo
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Subcortical mapping of white matter tracts (WMTs) subserving complex processes as movement, language and cognition is critical in glioma surgery. Continuous dynamic mapping (CDM) is an indispensable tool for mapping of the corticospinal tract (CST). There is, however, no widespread method for CDM of more advanced brain functions. MATERIAL AND METHODS Patients undergoing awake craniotomy for diffuse gliomas at the Oslo University Hospital with the use of neuronavigation, diffusion tensor imaging (DTI) and CDM coupled with structured evaluation as well as intraoperative magnetic resonance imaging (iMRI) were included in a retrospective analysis. Subcortical CDM was conducted when resection became close to the arcuate fasciculus (AF) and the frontal aslant tract (FAT) with clinical testing using language paradigms and Stroop task. The current was delivered through a monopolar suction probe applying a modified Taniguchi technique with short train of pulses. The spatial relationship between the stimulation response and the examined tracts was determined by measuring the shortest distance between the resection cavity and the relevant white matter tracts (WMTs) using iMRI DTI. RESULTS Twenty IDH-mutant and eight IDH wild type gliomas operated 2021-2023 were included in the analysis. Subcortical CDM of the AF and the FAT proved to be amenable as both language function and the ability to perform Stroop test were affected when the stimulation site gradually became close (&amp;lt; 1 cm) to the examined tracts. Positive stimulation response was verified by repeat challenge. The stimulation intensity was thereafter reduced in a stepwise fashion when there was a consistent hesitation in the patient’s response. Resection was continued until the tumor border was reached and not beyond the threshold of 3mA. The threshold of stimulation intensity correlated to the minimal distance from the resection cavity to the delineated WMTs. We did not observe any seizure activity induced by CDM. CONCLUSION We have experienced subcortical CDM to be a safe and reliable method, where distance to identified WMT appear to be correlated to the applied stimulation intensity.
P07.14.A OBSERVATIONS FROM THE FIRST 100 CASES OF INTRAOPERATIVE MRI - EXPERIENCES, TRENDS AND SHORT-TERM OUTCOMES IN PEDIATRIC VERSUS ADULT NEUROSURGICAL POPULATION
Authors: H Barchéus, C Peischl, I M Björkman-Burtscher, C Pettersson, D Nilsson, D Farahmand, J Eriksson, T Skoglund, A Corell
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The intraoperative MRI (iMRI) at Sahlgrenska University Hospital installed in 2017 was the first introduced in Sweden. Herein, we present a single center study with our observations from the first 100 patients undergoing neurosurgery in the dedicated iMRI surgical theater. METHODS Patients undergoing surgery in the 3T iMRI hybrid surgical theatre at our neurosurgical department between December 2017 to May 2021 were included after informed consent. Demographic, clinical, surgical, histological, radiological and outcome parameters, as well as variables related to iMRI, were retrospectively collected and analyzed. Patients were subdivided into adult and pediatric cohorts. RESULTS A variety of neurosurgical procedures were performed; resection of tumors and epileptic foci, endoscopic skull base procedures including pituitary lesions, deep brain stimulation (DBS), laser interstitial thermal therapy (LITT) and biopsies. Mean age was 32 years (range 0-81 years), 41 patients were pediatric and 42% were female. An iMRI scan was carried out in 96% of cases and led to continuation of surgery in 50 percent of cases, mainly due to visualized remaining pathological tissue. Median time to iMRI from intubation was 280 minutes and median total duration of surgery was 445 minutes. The majority of patients experienced no postoperative complications (70%), 13 patients suffered permanent postoperative deficits, predominantly visual. CONCLUSION We demonstrate demographics, clinical, surgical and radiological variables from the first 100 patients planned for surgery in the iMRI surgical theatre after INTRODUCTION in 2017. We found that iMRI was performed in almost all cases. In the pediatric cohort, tumors and epileptic focus were main indications for surgery. In adults, indications were intrinsic brain tumors, transsphenoidal pituitary tumor and DBS. Utilization from a resource and patients perspective appears to be most beneficial in tumor surgeries (specially pediatric), epileptic surgery and DBS.
P11.08.B R-MPV THERAPY FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA; SINGLE CENTER RETROSPECTIVE ANALYSIS
Authors: H Nagashima, K Tanaka, S Yamanishi, T Sasayama
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Whole brain radiation therapy (WBRT) to primary central nervous system lymphoma (PCNSL) correlate with brain atrophy and leukoencephalopathy, negatively impacting cognitive function and quality of life. R-MPV with reduced WBRT or without WBRT has recently been reported to improve the outcomes of PCNSL. Here we retrospectively analyzed newly diagnosed PCNSL patients to compare the outcome and toxicity of R-MPV therapy with these of WBRT following R-MTX therapy in a real-life setting. MATERIAL AND METHODS Sixty newly histological diagnosed PCNSL patients were retrospectively evaluated. Clinical data from the database included patient characteristics, response rate, adverse effects, overall survival and radiological brain atrophy at 1 year; whole brain volume (mm2) calculated from BainLab automatically. Thirty-one patients were received WBRT (30Gy) following R-MTX therapy (R-MTX-RT group) and 29 patients were received R-MPV therapy (R-MPV group). RESULTS The mean age at symptom onset was significantly younger in R-MTX-RT group than in R-MPV group (64 vs 74 years, p=0.014). Complete response rate after chemotherapy was higher in R-MPV group (58% in R-MTX-RT group and 88% in R-MPV group). However, overall survival was not significant difference (53.5 month in R-MTX-RT group, 52.7 month in R-MPV group). Three patients of 31 (9.6%) in R-MTX-RT group and 6 patients (20%) in R-MPV group were not able to complete the chemotherapy regimen. Notably, patients &amp;gt;75 years of age sometimes had severe adverse effect with R-MPV therapy. Treatment rerated death was not significant difference in both group (3% in R-MTX-RT vs 13% in R-MPV group, Fisher’s exact test p=0.19). Brain atrophy at 1 year was significantly lesser in R-MPV group than in R-MTX-RT group (R-MTX group, n=17; 4.03%, R-MPV group, n=15; 0.95%, p=0.005). CONCLUSION R-MPV therapy has benefit of avoiding WBRT in PCNSL patients. However, elderly patients exhibit increased risk for adverse events of R-MPV.
OS10.8.A APPLICATIONS OF NOVEL FFPE BASED TECHNOLOGIES FOR THE DIAGNOSTICS OF GLIOMAS
Authors: M Ritter, C Blume, B Patel, Y Tang, A Patel, N Berghaus, Z Seferbekova, P Sievers, C Herold-Mende, W Wick, M Gerstung, A von Deimling, F Sahm
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Due to the lack of consistent tumour-cell specific markers, the diffuse brain invasion of glioblastoma (GB) presents a significant diagnostic challenge, especially for specimens with a low tumour cell fraction or scarce tissue. The only common alteration found in most GB is the gain of chromosome 7 and loss of chromosome 10. The emergence of new technologies such as spatial and single nucleus transcriptomics that allow for detection of copy number alterations (CNVs) may allow us to push the diagnostic boundaries. MATERIAL AND METHODS We performed 10x Visium spatial transcriptomic analysis of FFPE tissue from bulk resections of 14 FFPE GB and stereotactic biopsies of 6 GB, 7 IDH mutant astrocytomas, 4 oligodendrogliomas and 1 diffuse glioma NOS. Visium tissue spots were then deconvolved using data from single nucleus transcriptomic data from nuclei isolated from FFPE tissue. Fresh frozen and FFPE single nucleus transcriptomic libraries were also generated from 4 GB with matching fresh-frozen and FFPE tissue available. RESULTS The infiltration zone, the tumour core and healthy brain tissue could be differentiated using the inferred CNVs of chromosome 7 and chromosome 10. Additionally, inferred CNVs of tissue fragments smaller than 1 mm2 were in accordance with Infinium MethylationEPIC array analysis (a well-established method for CNV detection) from the same tumour tissue. Using the spatial transcriptomics approach, the loss of chromosome 1p and 19q, which is characteristic for oligodendroglioma was also detected. To overcome the low resolution of Visium, deconvolution approaches using a single cell dataset can be used to determine the tumour content of a given tissue more precisely. To test if the single nuclei data from FFPE samples is suitable for deconvolution of spatial transcriptomics, we compared fresh-frozen and FFPE single nuclei data from matching tumours. As expected, FFPE and fresh frozen nuclei clustered together according to cell types and tumours in the UMAP space. CONCLUSION Spatial transcriptomics can be useful for brain tumour diagnostic workup, especially in cases where a limited amount of tissue prevents analysis by standard molecular diagnostic METHODS . Additionally, CNVs inferred from the spatial data as well as the spatial expression of marker genes help to better distinguish tumour infiltration zones from the core tumour and healthy brain tissue in the case of GB. This analysis can be further supported by deconvolution with a reference set generated from single nucleus transcriptomic analysis of FFPE tissue.
P11.69.B INTRAVENOUS THROMBOLYSIS WITH OR WITHOUT ENDOVASCULAR TREATMENT FOR SUSPECTED ISCHEMIC STROKE IN PATIENTS WITH INTRACRANIAL TUMORS
Authors: K Seystahl, N Martinez-Majander, A Salerno, M Beyeler, H Erdur, J P Marto, C Hametner, M Zedde, A Pezzini, R R Leker, V L Altersberger, G Costamagna, M Serôdio, L Migliaccio, R Pascarella, A Zini, L Razaqi, Y Béjot, S Jung, H Gensicke, V Padjen, P Ringleb, C H Nolte, M R Heldner, P Michel, S T Engelter, S Wegener, M Weller
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND: AND OBJECTIVES Intravenous thrombolysis (IVT) for suspected ischemic stroke in patients with intracranial neoplasms is off-label. However, data on risks of intracranial hemorrhage (ICH) is scarce. METHODS In a multicenter registry-based analysis within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration, we assessed frequencies of symptomatic and fatal ICH after IVT for suspected ischemic stroke in patients with intracranial tumors by descriptive statistics and analyzed associations with clinical and imaging characteristics by binary logistic regression. Definition of symptomatic ICH was based on the clinical criteria of the European Cooperative Acute Stroke-II trial including hemorrhage at any site in cranial imaging and concurrent clinical deterioration. RESULTS Screening data of 21,289 patients from 14 centers, we identified 105 patients receiving IVT, among them 29 patients (28%) with additional endovascular treatment, with suspected, i.e. imaging-based, or histologically confirmed diagnosis of intracranial tumors. Among 104 patients with CT or MRI after IVT available, symptomatic and fatal ICH were observed in nine and four patients (9% and 4%). Among 82 patients with suspected or confirmed meningioma, symptomatic and fatal ICH occurred in six and three patients (7% and 4%). In 18 patients with intra-axial suspected or confirmed primary or secondary brain tumors, there was one symptomatic nonfatal ICH (6%). Out of four patients with tumors of the pituitary region, two patients (50%) had symptomatic ICH including one fatal ICH (25%). Tumor size was not associated with occurrence of symptomatic ICH (Odds ratio 2.8, 95% CI 0.3-24.8, p=0.34). CONCLUSION In our dataset from routine clinical care, we provide insights on the safety of IVT for suspected ischemic stroke in patients with intracranial tumors, a population that is commonly withheld thrombolysis in clinical practice and prospective trials. Except for a potential high risk of symptomatic ICH after IVT in patients with tumors of the pituitary region, frequencies of symptomatic ICH in patients with intracranial tumors in our cohort appear to be in the upper range of rates observed in previous studies within the TRISP cooperation. These results may guide individual treatment decisions in patients with acute stroke and intracranial tumors with potential benefit of IVT.
P17.12.B FEASIBILITY OF PROLYL OLIGOPEPTIDASE (PREP) AS TUMOR BIOMARKER IN GLIOBLASTOMA PATIENTS: A PILOT STUDY
Authors: G Casili, M Caffo, S Scuderi, R Basilotta, M Lanza, A Filippone, I Paterniti, M Campolo, S Cuzzocrea, E Esposito
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Prolyl oligopeptidase (PREP) is a serine protease that hydrolyzes biologically active oligopeptides on their carboxyl side. PREP has been connected with multiple physiological and pathological conditions. Moreover, increased PREP activities have been found in tumors, although its involvement in the modulation of cancer mechanism is still unclear. Thus, the identification of PREP and clarification of its clinical significance are important for improving the diagnosis and treatment of brain tumors. The purpose of this study was to analyze the expression of PREP and its diagnostic and prognostic value in patients with Glioblastoma (GBM). Materials and METHODS In this study, GBM patients and controls were enrolled and clinical data and PREP expression, from serum and biopsies, were collected. The relationships between PREP, Protein phosphatase 2A (PP2A), STAT3 and Transforming growth factor-β (TGF- β) were also analyzed from clinical data. RESULTS Our study found that PREP was significantly upregulated in the serum samples and in biopsy from GBM patients compared with controls. This upregulation was negatively correlated with survival, but significantly correlated with age and Mindbomb Homolog-1 Index (MIB1). Also, PREP expression was inversely correlated with tumor suppressor PP2A in biopsy from GBM patients, while PREP protein levels resulted to be positively correlated with STAT3 and TGF-β protein expression. CONCLUSION s: The detection of PREP in serum and biopsies have the potential to serve as diagnostic and prognostic biomarker in GBM patient. The findings may provide diagnostic and therapeutic target for GBM.
P11.23.A GLIOBLASTOMA MOLECULAR CORRELATES OF SEIZURE OCCURRENCE/RECURRENCE AFTER SURGERY: THE ROLE OF P53 MUTATION
Authors: P Mattioli, E Cella, A Donniaquio, R Aloisio, R Mancini, F Calizzano, V Costa, F Villani, C Dellepiane, C Genova, S Vecchio, G Zona, P Fiaschi, M Truffelli, F Giannelli, S Barra, C Satragno, L Barletta, M Donegani, S Caneva, P Nozza, E Bennicelli, D Arnaldi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The integration of molecular data and histology changed the diagnostic approach and prognostic characterization for patients with brain tumors. The aim of this study is identify molecular risk factors associated with seizure occurrence and/or recurrence after surgery in patients with brain glioblastoma. MATERIAL AND METHODS Patients with brain glioblastoma were consecutively enrolled and underwent brain surgery, followed by histopathological and molecular evaluation. Immuno-histochemical, molecular (synaptophysin, GFAP, ATRX, p53, ki67 index and MGMT gene promoter methylation) and clinical (age, sex and seizure occurrence/recurrence before and/or after surgery) data were collected. Histopathological and molecular features were compared between patients with and without seizure occurrence/recurrence after surgery. A step-backward logistic regression was performed to investigate the association between molecular features and seizure occurrence/recurrence. RESULTS 100 patients (age 59.51±1.23, 65 males) were enrolled. Forty-nine patients had seizures before surgery. After surgery, 40 patients (age 59.43±1.64, 27 males) had seizure occurrence/recurrence, while 60 (age 59.57±1.75, 38 males) had not. Patients with epilepsy (i.e., seizures before and/or after surgery) had lower synaptophysin (33.33%, p=0.008) and higher p53 (85%, p=0.038) mutation rate compared with patients without epilepsy. In the whole sample, seizure occurrence/recurrence after surgery was significantly associated with p53 mutation (OR: 3.9, CI 1.12-13.50, p=0.032) and seizure occurrence before surgery (OR: 5.3, CI 2.15-13.08, p&amp;lt;0.001). In patients without seizures before surgery, p53 mutation perfectly predicted seizure occurrence, therefore the OR was not computable. In fact, all patients without p53 mutation didn’t have seizure after surgery, while all patients that had seizure after surgery, also had p53 mutation (p=0.028). However, to note 71% patients with p53 mutation didn’t have seizure after surgery. CONCLUSION The p53 mutation is related with a high risk of seizure occurrence/recurrence after surgery in brain glioblastoma, even in patients that didn’t have seizures before surgery. Conversely, the absence of p53 mutation appears to protect against the occurrence of seizures. If confirmed, this result may help in the management of anti-seizure treatment after surgery in brain glioblastoma patients.